We are proposing a broad-based program to directly address the "Genomics to Health" initiative in the NIH roadmap and the NHGRI vision for the future. Our program will focus on the application of newly developed technology to address unanswered question in genomics and proteomics, specifically those relating to unmet medical needs. To accomplish this we will establish an Affymetrix High Throughput Microarray facility to automate all crucial steps of the process from sample handling through data analysis. The samples for this analysis will come from diverse sources, including blood. We will greatly extend our molecular barcode technology to highly multiplexed quantitation of expression, DNA content and methylation, alternative splicing, SNPs, mutation detection and pathogen detection as single tubes assays read simultaneously on a single microarray at an enormous cost reduction that could revolutionize clinical medicine. After establishing robust protocols for these studies, we plan to develop new technologies that will drive the next generation of genetic, genomic and molecular analyses of model organisms and clinical samples. These next generation technologies will focus on completeness and accuracy, throughput, minimal user intervention, portability and decreased cost. Our goal is a cost reduction of 10 to 1,000 fold for each technology; including 1) reusable magnetic microarrays, 2) charge perturbation signature devices, 3) portable multiplexed CMOS detectors, 4) microfluidic instruments for pathogen typing, and 5) a novel nanobiosensor for single molecule detection of metabolites. A crucial testbed for the technology breakthroughs has been our work with yeast as an experimental system. We will expand this work with several novel yeast projects that will illuminate both basic cell physiology but also serve as a launch pad for translational medicine. Our efforts include: 1) using humanized yeast to screen for inhibitors of human proteins, 2) developing a full-genome tiling array for unprecedented resolution of the transcriptome, and 3) studies on DNA variation and complex traits.